The present invention relates to a process for the transformation of 3-phenyl cinnamate to enantiomerically pure 3,3-diphenyl-2,3-epoxy propionate.
3,3-Diphenyl-2,3-epoxy propionates are important intermediate products for the synthesis of biologically active substances, such as are described in, for example, Patent Applications WO 96/11914, WO 97/38981, DE 1963046.3 and DE 19944049.2. Said references describe the production of these active substances via racemic and enantiomerically pure glycide esters. In the racemic process the glycide ester is provided by Darzen""s synthesis of glycide ester. The racemic process suffers from the drawback that in a subsequent stage the undesirable enantiomer must be separated, which gives rise to a loss in total yield.
In said process for the preparation of enantiomerically pure glycide esters, 3-phenyl cinnamates are used as starting materials, which are transformed by Jacobsen epoxidation. This variant has however the drawback that the enantiomeric purities attained are only ca 85% e.e. and clean-up of the products is very elaborate. Thus these known processes are only useful to a limited extent in manufacturing processes intended for use on an industrial scale.
It is thus an object of the present invention to provide a process to the production of 3,3-diphenyl-2,3-epoxy propionate, which guarantees high enantiomeric purity and can be used on an industrial scale.
We have found a process for the enantioselective production of glycide ester by
(a) dihydroxylation of a corresponding 3-phenyl cinnamate (II) by osmium (VIII) oxide catalysis in the presence of a Sharpless ligand and an oxidizing agent to form the dihydroxy ester (III),
(b) selective conversion of the hydroxy function in position 2 of the dihydroxy ester (III) to a leaving group,
(c) intramolecular substitution of the leaving group through the hydroxy function in position 3 to produce the glycide ester (I), 
in which
R1 denotes C1-C10 alkyl, aryl or arylalkyl, which may be substituted,
R2 denotes C1-C10 alkyl, aryl, arylalkyl, halogen, C1-C10 alkoxy, hydroxy, acyloxy, amide, or amine, which may be substituted,
n is 0 to 5.
The reaction step (a) is an asymmetrical dihydroxylation such as has been described, for example, by Sharpless. Sharpless dihydroxylation and the use thereof have been described in detail by H. C. Kolb, M. S. Van Niewenhze, and K. B. Sharpless, in Chem. Rev. 1994, 94, 2483, the contents of which are included herein by reference. An article by L. Ahrgren and L. Sutin in Organic Process Research and Development 1997, 1, 425-427 has shown that the reaction should basically be executable on a greater scale (upscaleable).
By an osmium (VIII) oxide catalyst is meant an oxygen compound of osmium showing a level of oxidation of +VIII; OsO4 and K2OsO2(OH)4 are preferred.
The osmium (VIII) oxide need not be used in a stoichiometric amount relatively to the substrate of formula (II) but can, as catalyst, be employed in very much smaller quantities, the spent catalyst being regenerated by an oxidizing agent.
The osmium (VIII) oxide catalyst is usually used in amounts of from 0.1 to 5 mol % and preferably from 0.1 to 2.5 mol %, based on the substrate of formula (II).
By Sharpless ligands are meant compounds which are chiral, possess a nitrogen-containing six-membered heterocycle, bind to OsO4, and accelerate OsO4-dependent dihydroxylation.
Such Sharpless ligands are preferably hydroquinine and hydroquinidine derivatives as disclosed, for example, in the above literature. Preference is given to hydroquinine-(1,4-phthalazine-diyl diether) (DHQ)2PHAL or hydroquinidine-(1,4-phthalazine-diyl diether) (DHQD)2PHAL or hydroquinine-(2,5-diphenyl-4,6-pyrimidine-diyl diether) (DHQ)2PYR or hydroquinidine-(2,5-diphenyl-4,6-pyrimidine-diyl diether) (DHQD)2PYR.
The choice of Sharpless ligand is naturally governed by the desired enantiomer (III). Depending on the side from which the attack by (II) on the double bond to be hydroxylated is to take place, a corresponding Sharpless ligand must be selected according to the known mechanistic rules of Sharpless.
Suitable oxidizing agents for step (a) are those materials which are capable of reconverting the osmium oxide reduced during dihydroxylation of the double bond to its active level of oxidation of +VIII, ie materials which permit reactivation of the dihydroxylation catalyst. Such oxidizing agents can be readily found by considering their electrochemical potential. Well suited oxidizing agents are, for example, oxygen, hydrogen peroxide, N-methylmorpholine-N-oxide (NMO), potassium hexacyanoferrate, the AD-mix described by Sharpless (J. Org. Chem., 1992, 57, 2768), or alternatively electochemical processes.
Further oxidizing agents are described, for example, by M. Schrxc3x6der, Chem. Rev. 1980, 80, 187-213.
The oxidizing agents used are preferably oxygen, hydrogen peroxide, N-methylmorpholine-N-oxide, potassium hexacyanoferrate, and electrochemical processes.
A particularly suitable mixture for use in an industrial reaction according to (a) has been found to be a mixture of from 0.1 to 1.5 mol % of K2OsO2(OH)4, from 0.1 to 3 mol % of hydroquinine-(1,4-phthalazine-diyl diether) (DHQ)2PHAL or hydroquinidine-(1,4-phthalazine-diyl diether) (DHQD)2PHAL or hydroquinine-(2,5-diphenyl-4,6-pyrimidine-diyl diether) (DHQ)2PYR or hydroquinidine-(2,5-diphenyl-4,6-pyrimidine-diyl diether) (DHQD)2PYR and from 100 to 300 mol % of NMO, always based on the amount of 3-phenyl cinnamate (II).
Suitable solvents used are mixtures of water with an organic solvent.
Particularly suitable mixtures have been found to be mixtures of water with alcohols, acetonitrile, and acetone in a ratio of from 0.1 to 5:1 w/w.
The reaction temperature is in the range of xe2x88x9220xc2x0 C. to 100xc2x0 C., temperatures below 75xc2x0 C. being preferred.
In order to transform the diol to an epoxide, there are added to the diol from 1 to 10 equivalents of a base and from 1 to 3 equivalents of a sulfonyl chloride, an azodioic derivative, or a carbodiimide. In particular, preferred bases are tertiary amines, and sulfonyl chlorides are preferred for generation of a leaving group.
To introduce the leaving group in reaction step (b) use is preferably made of sulfonyl chlorides such as methanesulfonyl chloride and toluenesulfonyl chloride.
The reaction can be carried out as a one-pot process without isolation of an intermediate stage or as a two-stage process with isolation of the precursor of the epoxide. A preferred embodiment is the one-pot process.
Solvents for (b) or (c) are preferably aprotic solvents of medium polarity such as toluene or dichloromethane.
The reaction takes place at temperatures ranging from xe2x88x9270xc2x0 C. to 100xc2x0 C. Preference is given to reaction temperatures between xe2x88x9210xc2x0 C. and 35xc2x0 C.
The production of the corresponding 3-phenyl cinnamates (II) is known to the person skilled in the art from standard works of organic literature.
The conversion of 1,2-diols to epoxides is well-known and is described, for example, in the textbook by J. March, Advanced Organic Chemistry, 1985, Wiley, pages 270 and 345.